Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K i of 2.2 nM at G...

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Published in:Bioorganic & medicinal chemistry 2008-06, Vol.18 (11), p.3301-3305
Main Authors: Chen, Chen, Chen, Yongsheng, Pontillo, Joseph, Guo, Zhiqiang, Huang, Charles Q., Wu, Dongpei, Madan, Ajay, Chen, Takung, Wen, Jenny, Xie, Qiu, Tucci, Fabio C., Rowbottom, Martin, Zhu, Yun-Fei, Wade, Warren, Saunders, John, Bozigian, Haig, Struthers, R. Scott
Format: Article
Language:English
Subjects:
Animals
Antagonist
Biological and medical sciences
CYP3A4
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Gonadotropin-releasing hormone
Gonadotropin-Releasing Hormone - antagonists & inhibitors
Haplorhini
Hormones. Endocrine system
Humans
Inhibition
Inhibitory Concentration 50
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Rats
Receptor
Receptors, LHRH - antagonists & inhibitors
Structure-Activity Relationship
Uracil - analogs & derivatives
Uracil - chemical synthesis
Uracil - pharmacokinetics
Zwitterion
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Summary:Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K i of 2.2 nM at GnRH-R and an IC 50 of 36 μM at CYP3A4.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2008.04.036